In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter
The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane. It acts as a master regulator of fatty acids β-oxidation and is kn...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3946 |
| _version_ | 1797620379433304064 |
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| author | Andrea Pasquadibisceglie Virginia Quadrotta Fabio Polticelli |
| author_facet | Andrea Pasquadibisceglie Virginia Quadrotta Fabio Polticelli |
| author_sort | Andrea Pasquadibisceglie |
| collection | DOAJ |
| description | The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane. It acts as a master regulator of fatty acids β-oxidation and is known to be involved in neonatal pathologies and cancer. The transport mechanism, also known as “alternating access”, involves a conformational transition in which the binding site is accessible from one side of the membrane or the other. In this study, through a combination of state-of-the-art modelling techniques, molecular dynamics, and molecular docking, the structural dynamics of SLC25A20 and the early substrates recognition step have been analyzed. The results obtained demonstrated a significant asymmetry in the conformational changes leading to the transition from the c- to the m-state, confirming previous observations on other homologous transporters. Moreover, analysis of the MD simulations’ trajectories of the apo-protein in the two conformational states allowed for a better understanding of the role of SLC25A20 Asp231His and Ala281Val pathogenic mutations, which are at the basis of Carnitine-Acylcarnitine Translocase Deficiency. Finally, molecular docking coupled to molecular dynamics simulations lend support to the multi-step substrates recognition and translocation mechanism already hypothesized for the ADP/ATP carrier. |
| first_indexed | 2024-03-11T08:41:34Z |
| format | Article |
| id | doaj.art-0c88992b81024d20b51c9d6a60d6615b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:41:34Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0c88992b81024d20b51c9d6a60d6615b2023-11-16T21:07:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244394610.3390/ijms24043946In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 TransporterAndrea Pasquadibisceglie0Virginia Quadrotta1Fabio Polticelli2Department of Sciences, University of Roma Tre, 00146 Rome, ItalyDepartment of Sciences, University of Roma Tre, 00146 Rome, ItalyDepartment of Sciences, University of Roma Tre, 00146 Rome, ItalyThe Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane. It acts as a master regulator of fatty acids β-oxidation and is known to be involved in neonatal pathologies and cancer. The transport mechanism, also known as “alternating access”, involves a conformational transition in which the binding site is accessible from one side of the membrane or the other. In this study, through a combination of state-of-the-art modelling techniques, molecular dynamics, and molecular docking, the structural dynamics of SLC25A20 and the early substrates recognition step have been analyzed. The results obtained demonstrated a significant asymmetry in the conformational changes leading to the transition from the c- to the m-state, confirming previous observations on other homologous transporters. Moreover, analysis of the MD simulations’ trajectories of the apo-protein in the two conformational states allowed for a better understanding of the role of SLC25A20 Asp231His and Ala281Val pathogenic mutations, which are at the basis of Carnitine-Acylcarnitine Translocase Deficiency. Finally, molecular docking coupled to molecular dynamics simulations lend support to the multi-step substrates recognition and translocation mechanism already hypothesized for the ADP/ATP carrier.https://www.mdpi.com/1422-0067/24/4/3946mitochondrial carriersSLC25A20carnitine/acylcarnitine carrierstructural dynamicssubstrate recognitionAlphaFold 2 |
| spellingShingle | Andrea Pasquadibisceglie Virginia Quadrotta Fabio Polticelli In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter International Journal of Molecular Sciences mitochondrial carriers SLC25A20 carnitine/acylcarnitine carrier structural dynamics substrate recognition AlphaFold 2 |
| title | In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter |
| title_full | In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter |
| title_fullStr | In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter |
| title_full_unstemmed | In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter |
| title_short | In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter |
| title_sort | in silico analysis of the structural dynamics and substrate recognition determinants of the human mitochondrial carnitine acylcarnitine slc25a20 transporter |
| topic | mitochondrial carriers SLC25A20 carnitine/acylcarnitine carrier structural dynamics substrate recognition AlphaFold 2 |
| url | https://www.mdpi.com/1422-0067/24/4/3946 |
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